HIV and tuberculosis (TB) are, along with malaria, the leading infectious causes of death worldwide and in sub-Saharan Africa.1 In 2008, there were 2 million deaths from AIDS and 1.8 million deaths from TB worldwide.2, 3 The HIV epidemic has fueled an increase in the incidence, prevalence and mortality due to TB in the past 3 decades. 15% of TB cases are HIV co-infected worldwide.3 4 78% of HIV-infected TB cases are in Africa.3 TB is the leading cause of death and opportunistic infection among persons living with HIV/AIDS (PLWHA). The HIV epidemic has challenged time-tested TB control methods that are now failing in high HIV prevalence settings.5 The World Health Organization (WHO) has recommended that the Three I's - intensified case-finding for TB (ICF), isoniazid preventive therapy (IPT) and infection control for TB -be targeted at PLWHA.6 ICF and IPT have not been adequately implemented in part due to the absence of sensitive, specific and rapid TB tests. The Cepheid GeneXpert System, a new diagnostic test for TB, is a self-contained sputum-processing and real-time PCR system to detect the M. tuberculosis complex as well as rifampin resistance.7 8 The GeneXpert is rapid, highly sensitive and specific, can be used as a point-of-care test, and has low human resource, laboratory and infection control requirements.7, 8 The overall objective of this proposal is to conduct a cluster randomized trial of the relative impact and costeffectiveness of screening algorithms based on symptom screening, point-of-care GeneXpert TB testing and sputum smear microscopy versus a routine approach of symptom screening and sputum smear microscopy on the effectiveness of ICF and IPT for reducing morbidity and mortality due to TB among HIV-infected Malawians. 12 public sector clinics in southern Malawi will be randomized to 1 of 2 algorithms for TB case detection as part of ICF and for exclusion of TB prior to IPT and ART initiation. Under the routine screening algorithm, newly diagnosed HIV-infected patients at a clinic will be screened for symptoms of TB and, if symptomatic, will provide sputum for smear microscopy. In the clinics assigned to the GeneXpert algorithm, patients will be screened for symptoms of TB, and if symptomatic, and will provide sputum for GeneXpert point-of-care TB testing and smear microscopy. Outcomes will be measured at the clinic level. The specific aims of this project are: (1) to compare the impact of using the routine screening and GeneXpert algorithms for TB case detection on TB- and HIV-related outcomes, (2) to compare the impact of using the routine screening and GeneXpert algorithms for exclusion of TB prior to initiation of IPT and ART on TB- and HIV related outcomes, and (3) to assess the relative cost-effectiveness of the routine screening and GeneXpert algorithms for TB case detection and exclusion of TB. The GeneXpert is a disruptive technology 9 that could allow TB/HIV programs in resource-limited settings to leapfrog over solid and liquid culture-based TB diagnostic algorithms, and to remove a key barrier to scale up of ICF and IPT.